Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

Silvia Martinelli (), Elmira A. Anderzhanova, Thomas Bajaj, Svenja Wiechmann, Frederik Dethloff, Katja Weckmann, Daniel E. Heinz, Tim Ebert, Jakob Hartmann, Thomas M. Geiger, Michael Döngi, Kathrin Hafner, Max L. Pöhlmann, Lee Jollans, Alexandra Philipsen, Susanne V. Schmidt, Ulrike Schmidt, Giuseppina Maccarrone, Valentin Stein, Felix Hausch, Christoph W. Turck, Mathias V. Schmidt, Anne-Kathrin Gellner, Bernhard Kuster and Nils C. Gassen ()
Additional contact information
Silvia Martinelli: Max Planck Institute of Psychiatry
Elmira A. Anderzhanova: University of Bonn
Thomas Bajaj: University of Bonn
Svenja Wiechmann: Technical University of Munich, Emil-Erlenmeyer-Forum 5
Frederik Dethloff: Max Planck Institute of Psychiatry
Katja Weckmann: Max Planck Institute of Psychiatry
Daniel E. Heinz: University of Bonn
Tim Ebert: University of Bonn
Jakob Hartmann: Harvard Medical School and McLean Hospital
Thomas M. Geiger: Technische Universität Darmstadt
Michael Döngi: University of Bonn
Kathrin Hafner: Max Planck Institute of Psychiatry
Max L. Pöhlmann: Max Planck Institute of Psychiatry
Lee Jollans: Max Planck Institute of Psychiatry
Alexandra Philipsen: University of Bonn
Susanne V. Schmidt: University of Bonn
Ulrike Schmidt: Rheinische Friedrich-Wilhelms-Universität Bonn
Giuseppina Maccarrone: Max Planck Institute of Psychiatry
Valentin Stein: University of Bonn
Felix Hausch: Technische Universität Darmstadt
Christoph W. Turck: Max Planck Institute of Psychiatry
Mathias V. Schmidt: Max Planck Institute of Psychiatry
Anne-Kathrin Gellner: University of Bonn
Bernhard Kuster: Technical University of Munich, Emil-Erlenmeyer-Forum 5
Nils C. Gassen: Max Planck Institute of Psychiatry

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy via the stress-responsive co-chaperone FK506-binding protein 51. We identify the matrix metalloproteinase 9 (MMP9) as one of the proteins secreted in response to stress. Using cellular assays and in vivo microdialysis, we further find that stress-enhanced MMP9 secretion increases the cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF). BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders.

Date: 2021
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DOI: 10.1038/s41467-021-24810-5

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